WO2002062785A1 - Derives de benzimidazole, leur procede de preparation et leur utilisation comme inhibiteurs de la tryptase - Google Patents

Derives de benzimidazole, leur procede de preparation et leur utilisation comme inhibiteurs de la tryptase Download PDF

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Publication number
WO2002062785A1
WO2002062785A1 PCT/EP2002/001221 EP0201221W WO02062785A1 WO 2002062785 A1 WO2002062785 A1 WO 2002062785A1 EP 0201221 W EP0201221 W EP 0201221W WO 02062785 A1 WO02062785 A1 WO 02062785A1
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alkyl
phenyl
group
formula
compounds
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PCT/EP2002/001221
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German (de)
English (en)
Inventor
Claudia Thies
Christine Braun
Pascale Arielle Jane-Josee Pouzet
Ralf Anderskewitz
Bernd Disse
Horst Dollinger
Hans Michael Jennewein
Herbert Nar
Kai Malte Hasselbach
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Publication of WO2002062785A1 publication Critical patent/WO2002062785A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to benzimidazoldenvate of the formula (I)
  • radicals X, R1, R 2 , R3 and R 4 can have the meanings given in the claims and in the description, processes for their preparation and the use of benzimidazoldenvates as medicaments, in particular as medicaments with tryptase-inhibiting activity.
  • Benzimidazoldenvate are known from the prior art as active ingredients with valuable pharmaceutical properties.
  • international patent application WO 98/37075 also discloses benzimidazoles which, owing to their thrombin-inhibiting action, can be used effectively to prevent and treat venous and arterial thrombotic diseases.
  • the object of the present invention is to provide new tryptase inhibitors which, owing to their tryptase-inhibiting properties, can be used to prevent and treat inflammatory and / or allergic diseases , Detailed description of the invention
  • benzimidazoldenvate of the formula (I), in which the radicals R 1 , R 2 , R 3 and R 4 can have the meanings given below, have a tryptase-inhibiting action and can be used according to the invention for the prevention and treatment of diseases in which tryptase inhibitors can have a therapeutic benefit.
  • R 1 is a residue selected from the group C-
  • 2-Alkoxy-phenoxy may be substituted, or
  • Phenyl-C-C-12-alky 1 which may be one, two or three times by one or more of the radicals hydroxy, C-
  • -Ci2-Alkoxycarbonyl or CF3 may be substituted, or one directly or via a C-
  • R 3 represents a hydrogen atom or a C-
  • R 4 is a radical of the formula (A)
  • W represents N or CH
  • R 5 and R 6 each independently represent a hydrogen atom or a group of the formula
  • NH 2 may be substituted can, n is 0 or 1; optionally in the form of their tautomers, their racemates, their enantiomers, their
  • branched and unbranched alkyl groups with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, particularly preferably with 1 to 6 carbon atoms, in particular with 1 to 6, are alkyl groups (also insofar as they are part of other radicals, in particular alkoxy) 4 carbon atoms considered.
  • alkyl groups also insofar as they are part of other radicals, in particular alkoxy 4 carbon atoms considered.
  • the following are mentioned: methyl, ethyl, propyl, butyl, pentyl, hexyl etc.
  • the abovementioned designations propyl, butyl, pentyl or hexyl encompass all of the possible isomeric forms.
  • propyl includes the two isomeric residues n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert-butyl, the term pentyl, iso-pentyl, neopentyl etc.
  • Haloalkyl groups are, unless otherwise defined, branched and unbranched Haloalkyl groups with 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, particularly preferably with 1 to 3 carbon atoms, which are substituted by at least one halogen atom, in particular fluorine atom, are considered.
  • Fluorinated radicals of the formula are preferred
  • Examples include: trifluoromethyl, trifluoromethoxy, difluoromethoxy, perfluoroethyl, perfluoropropyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1, 1, 1-trifluoroprop-2-yl, etc.
  • Alkenyl groups are branched and unbranched alkenyl groups with 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, in particular 2 to 4 carbon atoms, insofar as they have at least one double bond, for example also alkyl groups mentioned above, insofar as they have at least one double bond, such as vinyl (provided that no volatile enamines or enol ethers are formed), propenyl, isopropenyl, butenyl, pentenyl, hexenyl.
  • Alkynyl groups are alkynyl groups with 2 to 12 carbon atoms, preferably 2 to 6
  • Carbon atoms in particular 2 to 4 carbon atoms, insofar as they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl.
  • Halogen is generally referred to as fluorine, chlorine, bromine or iodine.
  • the term "5- or 6-membered nitrogen, oxygen and / or sulfur-containing heterocyclic group" as used with respect to radical B generally stands for an aromatic or saturated radical with 5 or 6 ring atoms, at least one ring atom is a heteroatom selected from the group N, O and S, which can optionally be condensed with a further ring system.
  • the term "5- to 8-membered heterocycle" as used for the group, the R 5 and R 6 together with the enclosed nitrogen atom is usually a saturated nitrogen-containing radical having from 5 to 8 ring atoms, optionally containing one or can have several heteroatoms selected from the group N, O and S.
  • heterocyclic groups are acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, azanaphthacenyl,
  • Hydroimidazolyl hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, Imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl.
  • Benzotriazepinonyl Benzotriazolyl, Benzoxadiazinyl, Dioxadiazinyl, Dithiadazolyl, Dithiazolyl, Furazanyl, Furoxanyl, Hydrotriazolyl, Hydroxytrizinyl, Oxadiazinyl, Oxadiazolyl, Oxathiazinonylyl, Titrazolyl, Tetraazylylidyl, Pentazolylidyl, Tetrazylylidylylazylidyl, Tetrazolylidylylazidylylidonyl, Tetrazolylidylylidonyl, Pentazolylidylylidonyl, Tetradylylidylylidonyl Thiadiazolyl, thiadioxazinyl, thiathazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinediony
  • 5-, 6- or 7-membered, saturated or unsaturated heterocycles which contain nitrogen, oxygen or sulfur as heteroatoms Unless otherwise described in the definitions, furan, tetrahydrofuran, tetrahydrofuranone, ⁇ -butylrolactone, ⁇ -pyran, ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrrole, pyrrole, Pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine,
  • Piperazine triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole, pyrazolidine, where the heterocycle can be substituted as indicated in the definitions.
  • n is preferably 1.
  • R5 is preferably naphthyl, in particular naphth-2-yl, pyridyl, in particular pyrid-2-yl or pyrid-3-yl or a phenyl group optionally substituted by one or two halogen atoms, in particular selected from the formula
  • i represents a fluorine, chlorine, bromine or iodine atom
  • L 2 and L 3 each independently represent a hydrogen, fluorine or chlorine atom.
  • R 1 is a C 1 -C 6 -alkyl group, in particular methyl, ethyl, propyl or butyl, which may be one, two or three times through one or more of the hydroxyl, C-
  • R 1 is a C 1 -C 6 -alkyl group, in particular methyl, ethyl, propyl or butyl, which may be one, two or three times through one or more of the hydroxyl, C-
  • R 4 is a radical of the formula (A)
  • A is NR 6 ,
  • R 5 is a C-
  • Benzyl group means, these groups in each case optionally selected from the group halogen, -OH, halo-C ⁇ -C4-alkyl, halo-C-
  • -C4-alkyl may be substituted, and
  • R6 represents a hydrogen atom or a C 1 -C 4 alkyl group.
  • R 4 is a radical of the formula (A1)
  • R 5 is a hydrogen atom or a C -] - C4-alkyl, C-
  • -C4-alkyl which is optionally one, two or three times by one or more of the radicals hydroxy, C-
  • -C4-Alkoxy, CF3, phenoxy, COOH, halogen, -CO (-C -C4-alkoxy or -C-C4-alkoxy-phenoxy may be substituted, R 2 -C ( NH) NH 2 or -CH2-NH2 means;
  • R 3 is methyl, -CH 2 -COOH, -CH2-COO- CjC ⁇ alkyl, naphthylmethyl, benzyl or
  • Pyridylmethyl which is substituted on the respective aromatic and heteroaromatic ring by a radical selected from the group Ci -Cß-alkyl, -NH2, -NH (C-
  • R 5 is methyl, ethyl, propyl, butyl, phenyl, naphthyl, pyridyl or benzyl, which is optionally selected from the group halogen, trifluoromethyl, trifluoromethoxy, methyl, -OH, methoxy, -NO2, phenyl, naphthyl, pyrrolidine by one or two radicals -1-yl, -NH2, -NH-methyl, -N (methyl) 2 , -NH-ethyl,
  • R6 is hydrogen, methyl, ethyl, propyl or butyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.
  • R 1 denotes methyl, ethyl, propyl or butyl, preferably methyl
  • R 3 is methyl, -CH 2 -COOH, -CH 2 -COO-ethyl, naphthylmethyl, benzyl or
  • R 5 is phenyl, naphthyl, pyridyl or benzyl, which is optionally selected from the group consisting of fluorine, chlorine, bromine, iodine and one or two radicals,
  • Trifluoromethyl, methyl, -OH, methoxy and phenyl can be substituted, R 6 is hydrogen or methyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.
  • R 3 is methyl, -CH 2 -COOH, -CH 2 -COO-ethyl, naphthylmethyl, benzyl or pyridylmethyl;
  • R 5 is phenyl, naphthyl, pyridyl or benzyl, which may optionally be substituted by one or two radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, -OH, methoxy and phenyl,
  • R6 is hydrogen or methyl, optionally in the form of their tautomers, their racemates or theirs
  • R 1 is methyl;
  • R 2 -C ( NH) NH 2 ;
  • R 3 is methyl, -CH2-COOH, -CH2-COO-ethyl, benzyl, naphth-1-ylmethyl or pyrid-
  • each R 3 is hydrogen, -CH 2 -COOH, -CH 2 -COO-ethyl, methyl, butyl, benzyl,
  • Pyridylmethyl or naphthalinylmethyl means, where the aromatic groups can each be substituted by Ci-Cß-alkyl, -NO2, -NH2, -NH-C-
  • R 5 is a C-
  • Pyridylcarbonyl group means, these groups in each case optionally by one or more, preferably one, two or three, in particular one or two radicals selected from the group halogen, -OH, -C -] - C4-alkyl, C-
  • -C4-alkyl) 2 may be substituted, and
  • R 6 represents a hydrogen atom or a methyl group, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.
  • the present invention furthermore relates to compounds which, owing to a functionality which can be split off in vivo, are only converted by the organism into the therapeutically active compounds of the general formula (I) after they have been taken by the patient. Such compounds are called prodrugs.
  • a further aspect of the present invention accordingly targets prodrugs of the formula (II)
  • R 7 is hydroxy, -COO-C-
  • CF3 can be substituted means, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.
  • Preferred prodrugs of the formula (II) are those in which
  • R 7 hydroxy, -COO-C-
  • OH, halogen or CF3 may be substituted, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.
  • R 7 hydroxy, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 2,2,2-
  • Trichloroethoxycarbonyl, butyloxycarbonyl, benzoyl, benzyloxycarbonyl or nicotinoyl means, optionally in the form of their tautomers, their racemates, their enantiomers, their
  • the present invention further aims at the use of the compounds of the general formula (I) defined above and on the prodrugs of the general formula (II) for the manufacture of a medicament for the treatment of diseases in which tryptase inhibitors can have a therapeutic benefit.
  • preference is given to the use of compounds of the general formula (I) mentioned above for the preparation of a medicament for the prevention and / or treatment of inflammatory and / or allergic Diseases.
  • the use of the compounds of the general formula (I) mentioned at the outset is particularly preferred for the production of a medicament for the prevention and / or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastrointestinal diseases, Crohn's disease , Ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
  • ARDS septic shock
  • arthritis also of interest is the use of the compounds of the general formula (I) mentioned at the outset for the production of a medicament for the prevention and / or treatment of diseases with remodeling processes in the respiratory tract and the lung parenchyma, such as chronic (obstructive) bronchitis and interstitial
  • Lung diseases such as idiopathic pulmonary fibrosis, fibrosing alveolitis, sarcoidosis and histiocytosis X and other fibrosing diseases such as scarring, collagenosis such as lupus erythematosus and scleroderma as well as arteriosclerosis, psoriasis and neoplasia.
  • reaction is optionally carried out in a solvent or solvent mixture such as acetic acid, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane.
  • a solvent or solvent mixture such as acetic acid, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane.
  • Suitable dehydrating agents are, for example, isobutyl chloroformate, tetraethyl orthocarboxylate, triethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, phosphorus oxychloride, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, 1-2-1-dihydrochloride EEDQ), 1, 2-dihydro-2 - / - propyloxy-quinoline-1-carboxylic acid - / - propyl ester (IIDQ),
  • N.N'-dicyclohexylcarbodiimide N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1 H-benzotriazol-1-yl) - 1, 1, 3, 3-tetramethyluronium tetrafluoroborate, 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N.N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride.
  • a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine may prove expedient.
  • the reaction is usually carried out at temperatures between 0 and 150 ° C., preferably at temperatures between 20 and 120 ° C.
  • the nitrobenzimidazole derivatives (3) obtainable according to the procedure described above can be reductively converted into the aminobenzimidazoles (4) (stage iii, scheme 1).
  • the nitro group is reduced to the compounds (3), for example, by catalytic hydrogenations in organic solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, optionally also in a mixture with dimethylformamide, ethyl acetate, dioxane or acetic acid, at elevated hydrogen pressure or at normal pressure at temperatures between 0-50 ° C, preferably at 20-40 ° C.
  • organic solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, optionally also in a mixture with dimethylformamide, ethyl acetate, dioxane or acetic acid, at elevated hydrogen pressure or at normal pressure at temperatures between 0-50 ° C, preferably at 20-40 ° C.
  • Common hydrogenation catalysts are suitable as catalysts. Palladium and Raney nickel are preferred. Palladium is preferably used in accordance with the invention. Palladium on carbon (5%) is particularly preferred as catalyst.
  • This reaction takes place in protic, water-miscible organic solvents such as short-chain alcohols (methanol, ethanol, isopropanol) or in a mixture of the abovementioned solvents with water, optionally with acetic acid, dimethylformamide or ethyl acetate.
  • the reaction is usually carried out at elevated temperature, preferably under reflux of the particular solvent or solvent mixture.
  • After complete conversion of the starting compounds (3) is worked up in the usual way.
  • the compounds (4) can be purified, for example, by crystallization from nonpolar organic solvents, such as diethyl ether or petroleum ether, optionally in a mixture with ethyl acetate.
  • the compounds (5) are formed according to scheme 2 by reaction with the compounds R -Nu, where Nu for a nucleofugal leaving group such as chlorine, bromine, iodine, methanesulfonate, methyl triflate, p -Toluenesulfonate etc. stands.
  • the compounds (5) can be obtained from the compounds (4) in the sense of reductive amination by reaction with appropriately substituted ketones or aldehydes under reductive conditions.
  • the reaction of compounds (4) with R 3 -Nu according to stage iv can be carried out as follows.
  • a compound (4) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and particularly preferably anhydrous, optionally absolute dimethylformamide.
  • a base and the corresponding alkylating agent R 3 -Nu are added to the solution thus obtained.
  • Suitable bases are the alkali or alkaline earth carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate.
  • the procedure is as follows.
  • a suitable solvent such as dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran or toluene
  • the compound (4) is dissolved and between 0-60 ° C, preferably at 20-40 ° C with the corresponding carbonyl compound in the presence of an acid, preferably one Carboxylic acid, particularly preferably a short-chain carboxylic acid, most preferably acetic acid.
  • a suitable reducing agent is then added.
  • Na [HB (OAc) 3], Na [BH 3 CN], NaBH 4 , Pd / CH 2 are preferred, Na [HB (OAc) 3J is preferred.
  • the product is purified by crystallization or chromatography on silica gel.
  • the compounds (IIIA) can be reacted with the amines according to stage vi to give the intermediates (III).
  • the compound (IIIA) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and particularly preferably anhydrous, optionally absolute dimethylformamide.
  • a base and the corresponding amine are added to the solution thus obtained. As the base come the alkali or
  • Alkaline earth carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate.
  • the reaction mixture is stirred for 0.5-8h, preferably 1-4h at elevated temperature, preferably at 50-120 ° C, especially under reflux of the solvent used. After complete sales, the usual way worked up and the crude product obtained purified by crystallization or chromatography on silica gel.
  • Formula (III), in which R 6 is different from hydrogen, can be obtained by alkylation with an alkylating reagent R 6 -X 3 (with X 3 : halide, mesylate, tosylate, etc.) or by reductive amination according to the methods described in Scheme 2 receive.
  • a compound of general formula (I) is obtained, for example, by treating a compound of general formula (III) with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol, optionally in a mixture with another organic solvent such as chloroform, nitrobenzene or toluene in the presence of an acid such as hydrochloric acid or by reacting an appropriate amide with a thalkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C and below Aminolysis with, for example, alcoholic ammonia solution.
  • an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol
  • another organic solvent such as chloroform, nitrobenzene or toluen
  • the compounds of the general formula (I) can be obtained by reacting a compound of the general formula (III) with sulfur nucleophiles such as, for example, hydrogen sulfide, ammonium or sodium sulfide, sodium hydrogen sulfide, Carbon disulfide, thioacetamide or bistrimethylsilylthioether, optionally in the presence of bases such as triethylamine, ammonia, sodium hydride or sodium alcoholate in solvents such as methanol, ethanol, water, tetrahydrofuran, pyridine, dimethylformamide or 1,3-dimethyl-imidazolidin-2-one at 20-100 ° C and subsequent treatment with a suitable methylating agent such as methyl iodide or dimethyl sulfate in a solvent such as acetonitrile or acetone at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C and subsequent treatment with ammonia, ammonium carbonate or ammonium chlor
  • the compounds of the general formula (I) according to the invention are obtainable by treating a compound of the general formula (IM) with lithium hexamethyldisilazide in a suitable organic solvent, e.g. Tetrahydrofuran at temperatures between -20 and 50 ° C, but preferably at 0-20 ° C and subsequent hydrolysis with dilute hydrochloric acid at 0-5 ° C.
  • a suitable organic solvent e.g. Tetrahydrofuran
  • Another alternative approach to compounds of general formula (I) is by treating a compound of general formula (III) with ammonium chloride and trimethylaluminum in a suitable organic solvent such as e.g. Toluene at temperatures between 20 and 150 ° C, but preferably at 110 ° C.
  • a compound of general formula (II) is obtained, for example, by treating a compound of general formula (III) (Scheme 3, step vii) with hydroxylamine in the presence of carbonates or alcoholates of the alkali or alkaline earth metals in solvents such as methanol, ethanol, n -Propanol or isopropanol, optionally in a mixture with dioxane or tetrahydrofuran.
  • the alcoholates can be prepared from the respective alkali metals or metal hydrides and the corresponding alcohol.
  • the reaction is preferably carried out at 20-100 ° C., particularly preferably at the boiling point of the solvent used.
  • Compounds of the general formula (II) are alternatively obtainable by treating a compound of the general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a Trialkyloxonium salt such as T ethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C and subsequent
  • Treatment with hydroxylamine in the presence of bases in a suitable alcohol such as methanol, ethanol, isopropanol etc. at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C.
  • a compound of the general formula (I) can be obtained, for example, from
  • the compounds of the formula (III) are valuable intermediates for the preparation of the benzimidazole derivatives of the general formula (I) according to the invention and of the prodrugs of the general formula (II) according to the invention.
  • the compounds according to the invention can be used as medicaments, in particular as medicaments with tryptase-inhibiting activity. Can be used wherever tryptase inhibitors can have therapeutic benefits.
  • fibrosis such as pulmonary fibrosis, fibrosing alveolitis and scarring, of collagenoses such as lupus erythematosus and scleroderma, and of arteriosclerosis, psoriasis and neoplasia ,
  • Methylamine solution taken up, 2.5 days at room temperature and 2 h at 40-
  • Ice water decomposes It is made alkaline with NH3 with stirring / cooling and stirred at room temperature for 1 h. The solid is filtered off, washed with water and recrystallized from DMF. Yield: 11.7 g (76.4%); Mp: 202-204 ° C.
  • the mixture is stirred until the starting material has completely dissolved and then kept overnight at 0-5 ° C.
  • the ethanol is at a maximum of 40 ° C. and the residue was taken up in 40 ml of an ethanolic ammonia solution saturated at 0 ° C.
  • N- ⁇ 2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazol-5-yl ⁇ -N- (4-tert-butylphenyl-methyl) -2-chloroacetamide was prepared according to Example 1, Stage f implemented with 4- (2-pyridyl) amino piperidine. The chromatographic purification was carried out on silica gel.
  • stage g N- ⁇ 2- [2- (4-cyanophenyl) ethyl] -1-methylbenzimidazol-5-yl ⁇ -N- (4-tert-butylphenylmethyl) -2- [4- (2-pyridylamino) piperid-1-yl] acetamide converted to the title compound.
  • the purification was carried out chromatographically on silica gel.
  • the residue is chromatographed on silica gel.
  • the methylated trifluoroacetamide is taken up in MeOH, with 10 mL conc. aqueous ammonia solution and stirred at 30-40 ° C for 4 h.
  • the methanol is distilled off, the residue is taken up in 75 ml of ethyl acetate, washed with water, dried and concentrated.
  • the product is crystallized from diethyl ether. Yield: 6.5 g (75%); Mp: 155-158 ° C.
  • stage e 2- [2- (4-cyanophenyl) ethyl] -1-methyl-5-methylamino-benzimidazole are reacted with chloroacetyl chloride.
  • the purification was carried out chromatographically on silica gel. Yield: 68%.
  • stage f was N- ⁇ 2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimizazol-5-yl ⁇ -N-methyl-2-chloroacetamide with 4- (2- Chlorophenyl) amino-1-piperidine and purified by column chromatography on silica gel. Yield: 86%.
  • Example 84 Nf 2-.2- (4-Aminobenzvl.-Ethvl] -1-methyl-benzimidazole-5-vl) -N-methyl-2- [4- (2-chloro-4-fluorophenylamino) piperide- 1-yl] -acetamide. ditrifluoroacetate
  • stage e 2- [2- (4- (tert-butyloxycarbonylamino) benzyl) ethyl] -1-methyl-5-methylamino-benzimidazole (2.1 g, 5.3 mmol) are reacted with chloroacetyl chloride.
  • the purification was carried out chromatographically on silica gel. Yield: 2.5 g (100%).
  • the compounds according to the invention are notable for their tryptase-inhibiting activity. Said ability to inhibit tryptase was tested according to the test description below. The determination is carried out in Tris HCl buffer (100 mM), which additionally contains calcium (5 mM) and heparin (100 mg / ml), at pH 7.4. The standard used is rh beta tryptase, which can be purchased, for example, from Promega. Np-Tosyl-Gly-Pro-Lys-para-nitroaniline serves as the substrate in a concentration of 0.6 mM. The substrate is digested by tryptase to produce p-nitroaniline, which can be measured at 405 nm.
  • An incubation time of 5 minutes and an incubation temperature of 37 ° C. are usually selected.
  • As enzyme activity 0.91 U / ml are used.
  • the determination is carried out in an auto analyzer (Cobas Bio) from Hofmann LaRoche.
  • the potential inhibitory substances are used in concentrations of 10 ⁇ M in the screening, the inhibition of tryptase being stated in percent. If the inhibition is over 70%, the IC 50 is determined (concentration at which 50% of the enzyme activity is inhibited).
  • the substrate is added to start the reaction, the formation of p-nitroaniline being taken as a measure of the enzyme activity after 5 minutes after testing the linearity.
  • the tryptase inhibitors according to the invention can be administered orally, transdermally, by inhalation or parenterally.
  • the compounds according to the invention are present here as active constituents in customary dosage forms, for example in compositions which essentially consist of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, coated tablets, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc.
  • An effective dose of the compounds according to the invention is between 1 and 100, preferably between 1 and 50, particularly preferably between 5-30 mg / dose in the case of oral use, and between 0.001 and.
  • intravenous or intramuscular use 50 preferably between 0.1 and 10 mg / dose.
  • Solutions which contain 0.01 to 1.0, preferably 0.1 to 0.5% active ingredient are suitable for inhalation.
  • the use of powders is preferred for inhalation application.
  • the compounds according to the invention as Infusion solution, preferably in a physiological saline or nutrient solution.
  • the compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active compounds. Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • auxiliaries for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • auxiliaries for example inert d
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers in order to achieve a depot effect or to avoid incompatibilities.
  • the coated tablet to achieve a depot effect can consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. You can also suspending aids or thickening agents such as sodium carboxymethyl cellulose, wetting agents, for example
  • Injection solutions are prepared in a customary manner, for example with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and are filled into injection bottles or ampoules.
  • the capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatin capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be produced, for example, by mixing them with carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • a therapeutically effective daily dose is between 1 and 800 mg, preferably 10-300 mg per adult.
  • the finely ground active ingredient, milk sugar and part of the corn starch are mixed together.
  • the mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of a suitable shape and size.
  • the finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate, which is dried and sieved.
  • the sodium carboxymethyl starch and the magnesium stearate are added, and the mixture is mixed and pressed into tablets of a suitable size.
  • the active ingredient, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water.
  • the moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve.
  • After adding magnesium stearate The active ingredient, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water.
  • the moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve.
  • magnesium stearate domed dragee cores with a
  • the dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • the substance and corn starch are mixed and moistened with water.
  • the moist mass is sieved and dried.
  • the dry granules are sieved and mixed with magnesium stearate.
  • the final mixture is filled into size 1 hard gelatin capsules.
  • the active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as the isotonic agent, the solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed ,
  • the ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.
  • the hard fat is melted.
  • the milled active substance is homogeneously dispersed at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

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Abstract

L'invention concerne des dérivés de benzimidazole à substitution carboxamide, de formule générale (I), dans laquelle les groupes X, R?1, R2, R3 et R4¿ ont la signification indiquée dans les revendications et dans la description. L'invention concerne également des procédés pour la préparation de ces dérivés ainsi que l'utilisation de ces derniers comme médicaments, notamment comme médicaments à effet inhibiteur de la tryptase.
PCT/EP2002/001221 2001-02-08 2002-02-06 Derives de benzimidazole, leur procede de preparation et leur utilisation comme inhibiteurs de la tryptase WO2002062785A1 (fr)

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DE10105628A DE10105628A1 (de) 2001-02-08 2001-02-08 Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE10105628.1 2001-02-08

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6855713B2 (en) 2001-09-08 2005-02-15 Boehringer Ingelheim Pharma Kg Benzimidazole derivatives, a process for their manufacture and use as a medicine
EP1918281A1 (fr) * 2006-11-02 2008-05-07 Laboratorios del Dr. Esteve S.A. Composé piperidine substitué par phenylamino, leur préparation et utilisation comme médicament

Citations (5)

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Publication number Priority date Publication date Assignee Title
WO1999024407A1 (fr) * 1997-11-10 1999-05-20 Array Biopharma, Inc. Composes inhibant l'activite de la tryptase
WO1999040072A1 (fr) * 1998-02-03 1999-08-12 Boehringer Ingelheim Pharma Kg Heterocycles benzo condenses a 5 chainons utilises comme agents antithrombotiques
WO2001014342A1 (fr) * 1999-08-20 2001-03-01 Boehringer Ingelheim Pharma Kg Derives de benzimidazol substitues aminocabonyle, leur procede de preparation et leur utilisation comme produit pharmaceutique
WO2001023360A1 (fr) * 1999-09-24 2001-04-05 Boehringer Ingelheim Pharma Kg Derives de benzimidazole portant comme substituant un arylsulfonamide et leur utilisation comme inhibiteurs de la tryptase
WO2001034572A2 (fr) * 1999-11-10 2001-05-17 Boehringer Ingelheim Pharma Kg Derive de benzimidazole substitues par carboxamide, leur procede de production et leur utilisation comme medicaments

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024407A1 (fr) * 1997-11-10 1999-05-20 Array Biopharma, Inc. Composes inhibant l'activite de la tryptase
WO1999040072A1 (fr) * 1998-02-03 1999-08-12 Boehringer Ingelheim Pharma Kg Heterocycles benzo condenses a 5 chainons utilises comme agents antithrombotiques
WO2001014342A1 (fr) * 1999-08-20 2001-03-01 Boehringer Ingelheim Pharma Kg Derives de benzimidazol substitues aminocabonyle, leur procede de preparation et leur utilisation comme produit pharmaceutique
WO2001023360A1 (fr) * 1999-09-24 2001-04-05 Boehringer Ingelheim Pharma Kg Derives de benzimidazole portant comme substituant un arylsulfonamide et leur utilisation comme inhibiteurs de la tryptase
WO2001034572A2 (fr) * 1999-11-10 2001-05-17 Boehringer Ingelheim Pharma Kg Derive de benzimidazole substitues par carboxamide, leur procede de production et leur utilisation comme medicaments

Non-Patent Citations (1)

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Title
CAUGHEY G H ET AL: "BIS(5-AMIDINO-2-BENZIMIDAZOLYL)METHANE AND RELATED AMIDINES. ARE POTENT, REVERSIBLE INHIBITORS OF MAST CELL TRYPTASES", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND, US, vol. 264, no. 2, 1993, pages 676 - 682, XP002064911, ISSN: 0022-3565 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6855713B2 (en) 2001-09-08 2005-02-15 Boehringer Ingelheim Pharma Kg Benzimidazole derivatives, a process for their manufacture and use as a medicine
EP1918281A1 (fr) * 2006-11-02 2008-05-07 Laboratorios del Dr. Esteve S.A. Composé piperidine substitué par phenylamino, leur préparation et utilisation comme médicament
WO2008052769A1 (fr) * 2006-11-02 2008-05-08 Laboratorios Del Dr. Esteve S.A. Composés de pipéridine à substitution phénylamino, leur préparation et leur utilisation en tant que médicaments

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